The effect of FUT-175 (Nafamstat Mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo.
FUT-175 is a synthetic protease inhibitor and an inhibitor of the classical and alternate pathways of complement activation. In human serum, FUT-175 inhibited C3a, C4a and C5a generation induced by heat aggregated IgG, zymosan and Cobra venom factor with IC50 values in the range of 3-43 microM depending on the stimulus and the fragments. To assess in vivo anti-inflammatory activity, inflammatory reactions induced in the skin of rabbits were quantitated by using 125I-albumin extravasation, 51Cr-labelled leukocyte accumulation and 86RbCl accumulation as a measure of hyperemia. Infusion of FUT-175 at 2 mg/kg/h inhibited all three parameters by 50-80% in dermal reactions induced by killed E. coli, zymosan, immune complexes, the reversed Arthus reaction, zymosan activated plasma (ZAP), f-norleu-leu-phe (FNLP) and LTB4. In contrast, the response to endotoxin (0.1 microgram) was not effected by FUT-175 treatment. The effect of FUT-175 was comparable to that of local or systemic therapy with indomethacin, but unlike indomethacin, the effect of FUT-175 was not reversed by local PGE2 administration. Furthermore, indomethacin and FUT-175 had additive anti-inflammatory effects. These results suggest that although FUT-175 is a potent inhibitor of C3a, C4a and C5a generation, it has novel and broad anti-inflammatory effects, possibly through actions in addition to complement inhibition as indicated by inhibition of FNLP-, LTB4- and ZAP-induced reactions.
Issekutz
A C
AC
Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Roland
D M
DM
Patrick
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RA
D000818:Animals; D001550:Benzamidines; D015926:Complement C3a / Q000096:biosynthesis*; D015934:Complement C4a / Q000096:biosynthesis*; D015936:Complement C5a / Q000096:biosynthesis*; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D005122:Exudates and Transudates / Q000276:immunology / Q000378:metabolism; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology*; D007457:Iodine Radioisotopes; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D011817:Rabbits; D012867:Skin / Q000276:immunology / Q000378:metabolism
D001550:Benzamidines; D003169:Complement Inactivator Proteins; D006146:Guanidines; D007457:Iodine Radioisotopes; D015926:Complement C3a; D015934:Complement C4a; D015936:Complement C5a; D007213:Indomethacin; C032855:nafamostat